First-in-human clinical trials

FTIH trials are discussed in the Guideline on strategies to identify and mitigate risks for first-in human clinical trials with investigational medicinal products, EMEA/CHMP/SWP/28367/07issued by the European Medicines Agency (EMEA), in 2007. 

Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products [5]... 

Muller PY, Brennan FR. Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies. Clin Pharmacol Ther. 2009 85(3) 247-258. 

As a compound proceeds into first-in-human clinical trials, the assay method reaches an apex in terms of performance. These methods require maximal sensitivity to be able to support dose escalation studies. The selectivity of the method is well established versus matrix components, concomitant medications, and metabolites. The assay is revalidated in the human matrices (plasma, serum, and urine) and will again meet well-established guidelines for inter- and intraday precision and accuracy. If significant changes are made to the method, a comparison of methods study will be conducted to understand the relative accuracy of the methods. After this benchmark, assay requirements, especially limit of quantitation, are usually less demanding and use of the assay becomes more routine, as it is applied again and again to additional clinical studies for pharmacokinetic support. 

Tibbitts J, Cavagnaro JA, Haller CA, Marafino B, Andrews PA, Sullivan JT. 2010. Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals. Regulatory Toxicology and Pharmacology 58 243-251. 

Table 5.17 Phase 1 first-in-human clinical trial of TG02 (3) in patients with advanced hematological malignancies.

The first protease inhibitor studied in human clinical trials was ciluprevir (BILN-2061), whose discovery was predicated on earlier studies that identified 54, a 6 amino acid N-terminal cleavage product of an NS5A/5B substrate, as a competitive inhibitor of NS3 [103,104], Although the development of ciluprevir was halted due to cardiotoxicity in animals, it demonstrated that a potent... 

Perhaps the greatest hurdle along the pathway of a molecule becoming a useful drug is the need to sequentially pass clinical trials. However, before a drug can be evaluated in human clinical trials, it must first successfully negotiate preclinical testing. This frequently involves five or six types of test, and is completed in non-human animals ... 

As described in Chapter 31, Phase I includes first-in-human (FIH) trials to provide information about the safety (tolerability) and pharmacokinetics of a new drug. These trials are usually conducted in healthy volunteers unless the trials involve certain cytotoxic drugs such those used in cancer and HIV treatments. It should be noted that Phase I-type clinical pharmacology trials, such as those to study pharmacokinetics in special populations, can and do occur throughout the clinical drug development process (see Chapter 1, Figure 1.1). 

ABT-594 evolved from several years of research at Abbott Laboratories on nicotinic acetylcholine receptor modulators, directed initially toward treatment of Alzheimer s disease, and subsequently toward novel agents for treatment of pain. ABT-594 represents the first of a new generation of nAChR modulators to be tested as an analgesic agent in human clinical trials. The outcome of these studies with respect to both efficacy and... 

SRT-501 represented the first in a novel class of SIRTl activators that have proven to be safe and well-tolerated in humans. Clinical trials in type 2 diabetic patients were reported to be underway. 

First-in-man clinical trials with the Cypher stent system were performed at the Institute Dante Pazzanese de Cardiologia in the year 2000, comparing a moderate-release cypher stent with a slow-release one in 15 human patients. At the time stent-technology had been an emerging field and this clinical trial helped establish the therapeutic benefits of DBS use by demonstrating slowed neointimal growth in stented patients [1]. 

It is very important to note that it is considered unethical to intentionally determine biocompatibility or biostability in human clinical trials. These parameters are to have been established before regulatory submission and the first human implant. Of course, should any untoward result be found clinically, or in prior preclinical tests, it must be reported according to FDA regulations. The clinical study is to determine the human safety and reliability of the new product, not its biocompatibility or biostability. The requirements for the development of clinical study plans can be found in the FDA Guidance [29]. 

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